Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome
Open accessAbstract
In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.
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Combination therapies in MDS including HDAC inhibitors, lenalidomide, pevonedistat, and anthracyclines have not improved results.
“Combination therapies in this setting have included HDAC inhibitors, 33 , 34 , 35 lenalidomide, 36 pevonedistat, 37 and anthracyclines 38 all without improved results.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [33]
The Discussion (page unavailable) says that adding ATRA showed no significant clinical benefit and that a randomized decitabine–valproic acid study found no survival improvement. But it also reports marginal improvements in response measures and says the superiority of azacitidine–HDAC inhibitor combinations remains unresolved. This source therefore does not establish the categorical claim that HDAC inhibitor combinations have not improved results; the other drug classes have separate citations in the citing sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAZA alone continues to represent standard of care in MDS because all recent studies have failed to improve median OS compared to monotherapy.
“AZA alone continues to represent the standard of care in MDS because all recent studies have failed to improve the median OS compared to monotherapy.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [33]
The Discussion says that the superiority of AZA/HDACi combinations over AZA alone remained questionable and that a randomized study using decitabine found no survival benefit. It also says no controlled study had prospectively tested AZA/HDACi against AZA alone. It does not establish that AZA alone was the standard of care in MDS or that all recent studies failed to improve median OS over AZA monotherapy. (LLM, conf=0.78)
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References 26 · Cited by 134
- Authors
- Raffoux, E., Cras, A., Recher, C., Boëlle, P.-Y., de Labarthe, A., Turlure, P., Marolleau, J.-P., Reman, O., Gardin, C., Victor, M., Maury, S., Rousselot, P., Malfuson, J.-V., Maarek, O., Daniel, M.-T., Fenaux, P., Degos, L., Chomienne, C., Chevret, S., & Dombret, H.
- Affiliations
- Assistance Publique – Hôpitaux de Paris (FR)
- Université Paris Diderot (FR)
- Département d'Hématologie, Hôpital Purpan, Toulouse
- Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris
- Centre Hospitalier Universitaire de Limoges (FR)
- Département d'Hématologie, Hôpital Nord, Amiens
- Département d'Hématologie, Centre Hospitalier Universitaire, Caen
- Centre Hospitalier Universitaire Henri-Mondor (FR)
- Département d'Hématologie, Hôpital Mignot, Versailles
- Hôpital d'instruction des Armées Percy (FR)
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2010-05-19
- Volume
- 1
- Issue
- 1
- Pages
- 34-42
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4053545
- OpenAlex
- W1605755748
- Cited by
- 134
- References
- 26
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 10 · 2018: 6 · 2017: 8 · 2016: 10 · 2015: 10 · 2014: 19 · 2013: 22 · 2012: 18
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Oncotarget (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- azacitidine, valproic acid, all-trans retinoic acid, high-risk acute myeloid leukemia, myelodysplastic syndrome, combination therapy, epigenetic modulation, DNA demethylation, FZD9, ALOX12, Calca, platelet response, complete remission, overall survival, relapsed/refractory disease
- MeSH terms
- Aged, Aged, 80 and over, Anticonvulsants, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, DNA, Neoplasm, Female, Humans, Male, Middle Aged, Myelodysplastic Syndromes, Tretinoin, Valproic Acid, Leukemia, Myeloid, Acute, Survival Rate, Polymerase Chain Reaction, Treatment Outcome, DNA Methylation, Epigenomics
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